Novel oxime azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators

ABSTRACT

The present invention relates to novel oxime azetidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Non-Provisionalpatent application Ser. No. 13/300,873, filed Nov. 21, 2011, whichclaims the benefit of U.S. Provisional Application Ser. No. 61/419,348,filed Dec. 3, 2010, all of which are incorporated here by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to novel oxime azetidine derivatives,processes for preparing them, pharmaceutical compositions containingthem and their use as pharmaceuticals, as modulators ofsphingosine-1-phosphate receptors. The invention relates specifically tothe use of these compounds and their pharmaceutical compositions totreat disorders associated with sphingosine-1-phosphate (S1P) receptormodulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

A group of novel oxime azetidine derivatives which are potent andselective sphingosine-1-phosphate modulators has been discovered. Assuch, the compounds described herein are useful in treating a widevariety of disorders associated with modulation ofsphingosine-1-phosphate receptors. The term “modulator” as used herein,includes but is not limited to: receptor agonist, antagonist, inverseagonist, inverse antagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁹R¹¹ orhydroxyl;R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R³ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁴ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁵ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁶ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁸ is halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;

L is O, S, NH or CH₂;

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule;R⁹ is H or C₁₋₈ alkyl;R¹⁰ is H or C₁₋₈ alkyl;R¹¹ is H or C₁₋₈ alkyl; anda is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein L is O, S or NH.

In another aspect, the invention provides a compound having Formula Iwherein L is O.

In another aspect, the invention provides a compound having Formula Iwherein L is S.

In another aspect, the invention provides a compound having Formula Iwherein L is CH₂.

In another aspect, the invention provides a compound having Formula IwhereinD is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula I,

wherein:

In another aspect, the invention provides a compound having Formula I,

wherein:

In another aspect, the invention provides a compound having Formula I,

wherein:

In another aspect, the invention provides a compound having Formula Iwherein

A is C₆₋₁₀ aryl;

B is C₆₋₁₀ aryl;

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁵ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁶ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;

a is 0 or 1;

L is O, CH₂, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula I,

wherein:

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁵ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁶ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ orhydroxyl;

a is 0 or 1;

L is O, CH₂, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein

A is C₆₋₁₀ aryl;

B is C₆₋₁₀ aryl;

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O, CH₂, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl; R⁷ is H;

a is 0;

L is O, CH₂, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl; R⁷ is H;

a is 0;

L is S; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl; R⁷ is H;

a is 0;

L is O; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl; R⁷ is H;

a is 0;

L is CH₂; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O, S or NH; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O; and

D is a group of formula

“*” indicates the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is O; and

D is a group of formula

“*” indicates the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R′ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is S; and

D is a group of formula

“*” indicates the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is S; and

D is a group of formula

“*” indicates the rest of the molecule.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is CH₂; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen or C₁₋₆ alkyl;

R² is H, halogen or C₁₋₆ alkyl;

R³ is H, halogen or C₁₋₆ alkyl;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is H or C₁₋₆ alkyl;

R⁶ is H or C₁₋₆ alkyl;

R⁷ is H;

a is 0;

L is CH₂; and

D is a group of formula

“*” indicates the point of attachment to the rest of the molecule.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₈cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl,cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid,phosphonic acid groups, sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by alkyl groups or halogen atoms.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be substituted by alkyl groups orhalogen atoms.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by alkyl groups.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic.

Heterocyclic ring moieties can be substituted by hydroxyl, alkyl groupsor halogen atoms.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic.Aryl can be substituted by halogen atoms, —OC₁₋₆ alkyl, —C₁₋₆ alkyl,—CN, —C(O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl) or —NH₂ or —NH(C₁₋₆alkyl) or hydroxyl groups. Usually aryl is phenyl. Preferredsubstitution site on the phenyl ring are the meta and para positions.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic    acid;-   1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic    acid;-   1-(4-{(1E)-N-[2-(3-methylphenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)azetidine-3-carboxylic    acid;-   1-(4-{[({(1E)-2-(3-chlorophenyl)-2-[(3,4-dimethylphenyl)thio]-1-methylethylidene}amino)oxy]methyl}benzyl)azetidine-3-carboxylic    acid;-   1-{4-[(1E)-N-{2-[(3,4-dimethylphenyl)thio]-2-(3-fluorophenyl)ethoxy}ethanimidoyl]benzyl}azetidine-3-carboxylic    acid;-   1-{4-[({[(1E)-2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)-1-methylethylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic    acid;-   1-(4-{(1E)-N-[2-(3-chlorophenyl)-2-(3,4-dimethylphenoxy)ethoxy]ethanimidoyl}benzyl)azetidine-3-carboxylic    acid.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts,P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica ChemicaActa-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation.

-   -   Therapeutic utilities of S1P modulators are Ocular Diseases: wet        and dry age-related macular degeneration, diabetic retinopathy,        retinopathy of prematurity, retinal edema, geographic atrophy,        glaucomatous optic neuropathy, chorioretinopathy, hypertensive        retinopathy, ocular ischemic syndrome, prevention of        inflammation-induced fibrosis in the back of the eye, various        ocular inflammatory diseases including uveitis, scleritis,        keratitis, and retinal vasculitis; Systemic vascular barrier        related diseases: various inflammatory diseases, including acute        lung injury, its prevention, sepsis, tumor metastasis,        atherosclerosis, pulmonary edemas, and ventilation-induced lung        injury;    -   Autoimmune diseases and immnuosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of Ocular Diseases: wet and dry age-relatedmacular degeneration, diabetic retinopathy, retinopathy of prematurity,retinal edema, geographic atrophy, glaucomatous optic neuropathy,chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome,prevention of inflammation-induced fibrosis in the back of the eye,various ocular inflammatory diseases including uveitis, scleritis,keratitis, and retinal vasculitis;

Systemic vascular barrier related diseases: various inflammatorydiseases, including acute lung injury, its prevention, sepsis, tumormetastasis, atherosclerosis, pulmonary edemas, and ventilation-inducedlung injury;

-   -   Autoimmune diseases and immnuosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made.

The following abbreviations are used in the general schemes and in thespecific examples:

-   THF tetrahydrofuran-   MPLC medium pressure liquid chromatography-   NMO 4-Methylmorpholine N-oxide-   CH₃CN acetonitrile-   CH₂Cl₂ dichloromethane-   TPAP Tetrapropylammonium perruthenate-   MeOH methanol-   NaCNBH₃ sodium cyanoborohydride-   CD₃OD deuterated methanol-   DMSO-d₆ deuterated dimethyl sulfoxide-   NaOMe sodium methoxyde-   EtOH ethanol-   NaBH₄ sodium borohydride-   MgSO₄ magnesium sulfate-   NH₄Cl ammonium chloride-   HCl hydrochloric acid-   DIBAL-H Diisobutylaluminium hydride-   Et₂O ether-   MeOH methanol-   K₂CO₃ potassium carbonate-   DMF N,N-dimethylformamide-   Et₃N triethylamine-   CuI cooper iodide-   PdCl₂(PPh₃)₂ Bis(triphenylphosphine)palladium(II) chloride-   NaH sodium hydride-   EtOAc ethylacetate-   AcOH acetic acid-   TFA trifluoroacetic acid-   NH₃ ammonia-   CDCl₃ deuterated chloroform-   n-Bu₄NOH Tetrabutylammonium hydroxide-   NH₂NH₂ hydrazine-   LAH or LiAlH₄ Lithium aluminium hydride-   DEAD diethyl azodicarboxylate-   Ph₃P triphenylphosphine

Synthetic Scheme for Obtained Compound of Formula I Wherein D is

General Procedure a for Obtaining Intermediate 1

The starting material, a carboxylic acid (7.82 mmol) prepared accordingto, Marvin J. et al, Journal of Medicinal Chemistry, 44, 4230-4251, 2001was dissolved in anhydrous ether (100 mL) at −10° C. A solution ofLiAlH₄ (3.9 mL, 2.0M in hexane, 7.82 mmol) was added slowly and thereaction mixture was stirred at room temperature for 4 hours. Thereaction was then quenched with aqueous NH₄Cl and extracted with ether.The combined organic layers were washed with H₂O and brine, then driedover Na₂SO₄. The solvent was removed under reduced pressure. Thecorresponding alcohol was obtained and isolated by MPLC using 10 to 20%ethyl acetate in hexane.

DEAD (2.58 ml, 40% in toluene, 5.94 mmol) was added dropwise at 0° C. tothis alcohol derivative (1.16 g, 4.57 mmol) with triphenylphosphine(1.44 g, 5.48 mmol), and N-hydroxyphthalimide (896 mg, 5.48 mmol) in THF(50 mL). The mixture was stirred at room temperature for 16 h andevaporated to dryness. The residue was purified by MPLC using 20-40%ethyl acetate in hexane to afford the corresponding N-alkoxyphthalimide.

A mixture of the above N-alkoxyphthalimide (2.0 g, 5 mmol) and hydrazinemonohydrate (0.25 mL, 5 mmol) in MeOH (30 mL) was heated under refluxfor 4 h. After cooling, the resulting suspension was filtered, and thefiltrate was evaporated. The residue was triturated with Et₂O andfiltered, and the filtrate was evaporated to dryness. The residue waspurified by MPLC using 10-20% ethyl acetate in hexane to give thecorresponding hydroxylamine Intermediate 1 type.

General Procedure B for Obtaining Intermediate 2

To the mixture of Intermediate 1 (1.15 g, 4.27 mmol) and1-(4-hydroxylmethyl) phenyl)ethanone (641 mg, 4.27 mmol) preparedaccording to Zhengqiang et al, Journal of Medicinal Chemistry, 50(15),3416-3419; 2007, in methanol (20 mL) were added 3 drops of HOAc. Thereaction solution was stirred at room temperature for 16 hours and thenevaporated to dryness. The corresponding alcohol compound was obtainedand purified by MPLC using 0-40% ethyl acetate in hexane.

The above alcohol (4.24 mmol) was mixed with NMO (1.24 g, 10.6 mmol),molecular sieve (600 mg) in AcCN (5 mL) and DCM (25 mL). A catalyticamount of TPAP (40 mg) was added. The resulting reaction mixture wasstirred at RT for 1 hour and evaporated to dryness. The aldehydeIntermediate 2 type was purified by MPLC using 0-10% ethyl acetate inhexane.

General Procedure C for Obtaining a Compound of Formula I fromIntermediate 2

An intermediate 2 (250 mg, 0.62 mmol), 3-azetidinecarboxylic acid (82mg, 0.81 mmol) and TEA (0.1 ml, 0.7 mmol) were mixed with MeOH (10 ml).Upon stirring at 60° C. for 90 min, the reaction solution was cooled toRT. NaBH₄ (50 mg, 1.35 mmol) was added and stirred at RT for 2 hour. Thereaction was quenched with 0.5 mL of water and concentrated to minimalamount. The compound of Formula I, was isolated by reverse phase MPLCusing 0 to 90% H₂O in AcCN.

Synthetic Scheme for Obtained Compound of Formula I Wherein D is

The compounds of Formula I wherein D is

are prepared according to procedures A, B and C as described above. Thecarboxylic acid staring material is replaced with a methyl ketoneprepared according to Marvin J. et al, Journal of Medicinal Chemistry,44, 4230-4251, 2001. The methyl ketone reacts and {4-[(aminooxy)methyl]phenyl}methanol prepared according to Fensholdt, Jef et al, WO200505417 according to the B procedure to afford the aldehydeIntermediate 3. Intermediate 3 is used in procedure C, as describedabove, to afford the compound of Formula I.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8; and Intermediates andreagent names used in the examples were generated with software such asChem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5SP1.

In general, characterization of the compounds is performed according tothe following methods: Proton nuclear magnetic resonance (¹H NMR) andcarbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on aVarian 300 or 600 MHz spectrometer in deuterated solvent. Chemicalshifts were reported as δ (delta) values in parts per million (ppm)relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm)and multiplicities were reported as s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad. Data were reported in the followingformat: chemical shift (multiplicity, coupling constant(s) J in hertz(Hz), integrated intensity).

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

Compounds 1 to 8 were prepared according to the general procedures A, Band C. The starting materials, intermediates and the results aretabulated below in Table 1 for each case.

TABLE 1 IUPAC name of the compound Starting material CompoundIntermediate ¹H NMR (Solvent; δ ppm) Compound 1

¹H NMR (300 MHz, CD₃OD) δ ppm 2.09 (s, 3 H) 2.14 (s, 3 H) 2.16 (s, 3 H)2.28 (s, 3 H) 2.79-2.89 (m, 1 H) 2.98- 3.08 (m, 1 H) 3.28-3.40 (m, 4 H)3.55 (t, J = 7.90 Hz, 2 H) 3.65 (s, 2 H) 4.29 (dd, J = 6.74, 2.05 Hz, 2H) 6.76 (d, J = 7.62 Hz, 1 H) 6.83 (s, 1 H) 6.88- 7.02 (m, 4 H)7.09-7.15 (m, 1 H) 7.30 (d, J = 8.20 Hz, 2 H) 7.57 (d, J = 8.20 Hz, 2H). Starting material 2-(3-methylphenyl)-3-(3,4-dimethylphenyl)propanoic acid Intermediate 1 ¹H NMR (300 MHz, CD₃OD)4-[3-(aminooxy)-2-(3- δ ppm 2.13 (s, 3H) 2.14 (s,methylphenyl)propyl]-1,2- 3H) 2.25(s, 3H) 2.64-2.82 dimethylbenzene (m,1H) 2.90-2.99 (m, 1 H) 3.12 (m, 1 H) 3.79 (d, J = 6.74 Hz, 2 H) 6.74 (d,J = 7.62 Hz, 1 H) 6.80 (s, 1 H) 6.88-6.95(m, 4H) 7.06-7.13 (m, 1 H).Intermediate 2 ¹H NMR (300 MHz, CD₃OD) δ4-{(1E)-N-[2-(3-methylphenyl)-3- ppm 2.12-2.19 (m, 9 H) 2.29 (3,4- (s, 3H) 2.81-2.92 (m, 1 H) dimethylphenyl)propoxy]ethan- 2.98-3.08 (m, 1 H)3.32- imidoyl}benzaldehyde 3.34(m, 1H) 4.36 (dd, J = 6.89, 1.61 Hz, 2 H)6.75-6.86 (m, 2 H) 6.89-7.05 (m, 4 H) 7.10- 7.17 (m, 1 H) 7.90 (d, J =8.20 Hz, 2 H) 7.81(d, J = 8.20 Hz, 2H)10.00 (s, 1 H). Compound 2

¹H NMR (300 MHz, CD₃OD) δ ppm 2.08 (s, 3 H) 2.14 (s, 3 H) 2.15 (s, 3 H)2.83 (m, 1 H) 3.00 (m, 1 H) 3.20 (hept, J = 8.36 Hz, 1 H) 3.32-3.38 (m,3 H) 3.51-3.56 (m, 2 H) 3.63 (s, 2 H) 4.31 (m, 2 H) 6.77 (d, J = 7.63, 1H) 6.83 (s, 1 H) 6.92 (d, J = 7.92 Hz, 1 H) 7.09-7.12 (m, 1 H) 7.15 (m,1 H) 7.18-7.22 (m, 2 H) 7.29 (d, J = 8.51 Hz, 2 H) 7.56 (d, J = 8.51 Hz,2 H). Starting material 2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propanoic acid Intermediate 3 ¹H NMR (300 MHz, CD₃OD) δ4-[3-(aminooxy)-2-(3- ppm 2.16 (s, 6 H) 2.61-2.84chlorophenyl)propyl]-1,2- (m, 1 H) 2.89-3.03 (m, 1 H) dimethylbenzene3.19 (m, 1 H) 3.81 (d, J = 6.45 Hz, 2 H) 6.75 (d, J = 7.91 Hz, 1 H) 6.81(s, 1 H) 6.92 (d, J = 7.91 Hz, 1 H) 7.04-7.26 (m, 4 H). Intermediate 4¹H NMR (300 MHz, CD₃OD) δ 4-{(1E)-N-[2-(3-chlorophenyl)-3- ppm 2.13 (s,3 H) 2.15 (s, 3 H) (3,4- 2.16 (s, 3 H) 2.80-2.90 (m, 1dimethylphenyl)propoxy]ethan- H) 2.97-3.07 (m, 1 H) 3.33-imidoyl}benzaldehyde 3.42 (m, 1 H) 4.37 (m, 2 H) 6.79 (d, J = 7.62 Hz, 1H) 6.84 (s, 1 H) 6.93 (d, J = 7.62 Hz, 1 H) 7.09-7.26 (m, 4 H) 7.79 (d,J = 8.5 Hz, 2 H) 7.87 (d, J = 8.5 Hz, 2 H) 9.98 (s, 1 H). Compound 3

¹H NMR (300 MHz, CD₃OD) δ ppm 1.70 (s, 3 H) 2.15 (s, 3H) 2.18(s, 3H)2.75-3.02 (m, 1 H) 3.15-3.27 (m, 2 H) 3.39 (t, J = 8.20 Hz, 2 H)3.53-3.61 (t, J = 8.20 Hz, 2 H) 3.67 (s, 2 H) 3.72 (t, J = 8.20 Hz, 1 H)5.08 (s, 2 H) 6.73 (d, J = 7.62 Hz, 1 H) 6.81 (s, 1 H) 6.91 (d, J = 7.62Hz, 1 H) 7.02-7.09 (m, 1 H) 7.14 (s, 1 H) 7.17-7.25 (m, 2 H) 7.27 (s, 4H). Starting material 3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butan-2-one Intermediate 5 ¹H NMR (300 MHz, CD₃OD)4-[({[(1E)-2-(3-chlorophenyl)-3- δppm 1.75 (s, 3 H) 2.13 (s, 3(3,4-dimethylphenyl)-1- H) 2.18 (s, 3 H) 2.83-2.93 (m,methylpropylidene]amino}oxy) 1 H) 3.14-3.23 (m, 1 H) 3.76methyl]benzaldehyde (t, J = 7.90 Hz, 1 H) 5.19 (s, 2 H) 6.703 (d, J =7.62 Hz, 1 H) 6.81 (s, 1 H) 6.88 (d, J = 7.62 Hz, 1 H) 7.05-7.11 (m, 1H) 7.14 (s, 1 H) 7.19-7.23 (m, 2 H) 7.44 (d, J = 8.50 Hz, 2 H) 7.85 (d,J = 8.50 Hz, 2 H) 9.99 (s, 1 H). Compound 4

¹H NMR (300 MHz, CD₃OD) δ ppm 1.71 (s, 3 H) 2.16 (s, 3 H) 2.18 (s, 3 H)2.84-2.93 (m, 1 H) 3.21 (s, 2 H) 3.37 (t, J = 8.20 Hz, 2 H) 3.56 (t, J =8.20 Hz, 2 H) 3.66 (s, 2 H) 3.76 (t, J = 7.9 Hz, 1 H) 5.08 (s, 2 H)6.69-6.79 (m, 4 H) 6.82 (s, 1 H) 6.92 (d, J = 7.62 Hz, 1 H) 7.27 (s, 4H). Starting material 3-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butan-2-one Intermediate 6 ¹H NMR (300 MHz, CD₃OD) δ4-[({[(1E)-2-(3,5-difluorophenyl)-3- ppm 1.75 (s, 3 H) 2.13 (s, 3 H)(3,4-dimethylphenyl)-1- 2.17 (s, 3 H) 2.83-2.93 (m, 1methylpropylidene]amino}oxy) H) 3.12-3.22 (m, 1 H) 3.79 (t,methyl]benzaldehyde J = 7.9 Hz, 1 H) 5.19 (s, 2 H) 6.69-6.84 (m, 5 H)6.90 (d, J = 7.62 Hz, 1 H) 7.44 (d, J = 8.20 Hz, 2 H) 7.84 (d, J = 8.20Hz, 2 H) 9.98 (s, 1 H). Compound 5

¹H NMR (300 MHz, CD₃OD) δ ppm 1.83-1.86 (m, 3 H) 2.17 (s, 3 H) 2.22 (s,3 H) 3.12- 3.27 (m, 1 H) 3.33-3.41 (m, 2 H) 3.50-3.59 (m, 2 H) 3.64 (s,2 H) 4.82-5.01 (m, 3 H) 6.96- 7.14 (m, 3 H) 7.14-7.34 (m, 8 H) Compound6

¹H NMR (300 MHz, CD₃OD) δ ppm 2.16 (s, 6 H) 2.18 (s, 3 H) 3.17-3.30 (m,2 H) 3.40- 3.54 (m, 3 H) 3.57-3.66 (m, 2 H) 3.72 (s, 2 H) 5.30 (t, J =6.30 Hz, 1 H) 6.94-7.03 (m, 2 H) 7.04-7.18 (m, 4 H) 7.25- 7.34 (m, 3 H)7.55 (d, J = 8.20 Hz, 2 H) Compound 7

Spectroscopic data. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.66 (s, 3 H) 2.11(m, 6 H) 3.07-3.22 (m, 3 H) 3.34 (br. s., 2 H) 3.51 (br. s., 2 H) 5.06(br. s., 2 H) 5.87 (s, 1 H) 6.69 (d, J = 8.20 Hz, 1 H) 6.83 (br. s., 1H) 6.95 (d, J = 8.20 Hz, 1 H) 7.12-7.28 (m, 4 H) 7.27- 7.47 (m, 4 H).Compound 8

Spectroscopic data. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.04 (s, 3 H) 2.08(s, 6 H) 2.99- 3.17 (m, 3 H) 3.24-3.39 (m, 2 H) 3.51 (br. s., 2 H) 4.33(dd, J = 4.40 Hz, 1 H) 4.44 (dd, J = 7.30 Hz, 1 H) 5.55-5.67 (m, 1 H)6.63 (m, 1 H) 6.75 (d, J = 2.64 Hz, 1 H) 6.90 (d, J = 8.20 Hz, 1 H) 7.26(d, J = 8.20 Hz, 2 H) 7.29-7.44 (m, 3 H) 7.49 (br. s., 1 H) 7.56 (d, J =8.20 Hz, 2 H).

Biological Data

Compounds were synthesized and tested for S1P1 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P1 receptor in cells stablyexpressing the S1P1 receptor.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nMGTP γ³⁵5, and 5 μg membrane protein in a volume of 150 μl. Testcompounds were included in the concentration range from 0.08 to 5,000 nMunless indicated otherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl-100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P in the presence of test antagonist at concentrationsranging from 0.08 to 5000 nM.

Table 2 shows activity potency: S1P1 receptor from GTP γ³⁵5: nM, (EC₅₀).Activity potency: S1P1 receptor from GTP γ³⁵5: nM, (EC₅₀),

TABLE 2 S1P1 IUPAC name EC₅₀ (nM)1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)- 17.51-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3- carboxylic acid1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1- 230methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3- carboxylic acid1-(4-{(1E)-N-[2-(3-methylphenyl)-3-(3,4- 16.5dimethylphenyl)propoxy]ethanimidoyl}benzyl)azetidine-3- carboxylic acid1-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4- 9.05dimethylphenyl)propoxy]ethanimidoyl}benzyl)azetidine- 3-carboxylic acid1-(4-{(1E)-N-[2-(3-chlorophenyl)-2-(3,4- 163.26dimethylphenoxy)ethoxy]ethanimidoyl}benzyl)azetidine- 3-carboxylic acid

What is claimed is:
 1. A compound having Formula I, its enantiomers, diastereoisomers, hydrates, solvates, crystal forms and individual isomers, tautomers or a pharmaceutically acceptable salt thereof,

wherein: R¹ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R² is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R³ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁴ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁵ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁶ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁷ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁸ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; L is O, S, NH or CH₂; D is a group of formula

“*” indicating the point of attachment to the rest of the molecule; R⁹ is H or C₁₋₆ alkyl; R¹⁹ is H or C₁₋₆ alkyl; R¹¹ is H or C₁₋₆ alkyl; and a is 0 or
 1. 2. A compound according to claim 1 selected from: 1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 3-(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid; 3-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid.
 3. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier.
 4. A pharmaceutical composition according to claim 3 wherein the compound is selected from: 1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 3-(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid; 3-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid.
 5. A method of treating a disorder associated with sphingosine-1-phosphate receptor modulation, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I

wherein: R¹ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R² is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R³ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁴ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁵ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁶ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁷ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; R⁸ is halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl, CN, C(O)R⁹, NR¹⁰R¹¹ or hydroxyl; L is O, S, NH or CH₂; D is a group of formula

“*” indicating the point of attachment to the rest of the molecule; R⁹ is H or C₁₋₆ alkyl; R¹⁹ is H or C₁₋₆ alkyl; R¹¹ is H or C₁₋₆ alkyl; and a is 0 or
 1. 6. A method of claim 5, wherein the pharmaceutical composition is administered to the mammal to treat ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases, various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection, ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains.
 7. The method of claim 6 wherein the mammal is a human 